Project Summary/Abstract The goal of this proposal is to directly measure electrical activity, BOLD response, CBF response, and CMRO2 change during task performance in MS. Our hypothesis is that electrical activity and CMRO2 will be related in all subjects, while electrical activity and BOLD will be related in healthy controls and not in MS patients. We also propose a simple method to correct for the uncoupling in MS, based on resting state fMRI. Specific aim 1 will determine simultaneously neuronal activity from EEG and BOLD signal and cerebral blood flow in fifteen MS patients and 15 age and sex matched healthy control subjects. Using MRI compatible EEG and our combined BOLD-ASL data acquisition, we can determine electrical activity and BOLD signal in response to a task. We hypothesize that BOLD signal during task performance will be highly correlated with electrical activity in healthy controls, but not in MS patients. Specific aim 2 will simultaneously measure CBF and BOLD signal changes during task performance and hypercapnia challenge in the same population. Our hypothesis is that the relationship of CBF change to CMRO2 change in MS patients will be lower in MS than healthy controls. Specific aim 3 proposes to use spontaneous BOLD fluctuations measured in a resting-state BOLD acquisition to generate calibrated fMRI activation maps. The resulting activation from the corrected BOLD activation will reflect the differences in electrical activity shown in aim 1. This project is part of an ongoing effort to assess the impact of the cerebrovascular effects of MS on the BOLD response in the brain. The clinical impact of this is to improve the utility of fMRI techniques in managing and assessing multiple sclerosis patients. Thus, this work addresses a significant need in the development of therapeutic treatments for multiple sclerosis (MS).